Skeletal Muscle

Enzyme Histochemistry and Immunohistochemistry: There is no question that frozen section histochemistry of unfixed muscle samples is the “gold standard” of muscle pathology. Skeletal muscle may be the one tissue in which the morphology of cells and cellular components is best appreciated in frozen sections (Fig. 15-11, B). Routine frozen section histochemistry on muscle includes a battery of stains applied to serial sections. Examples of many of these stains are illustrated in this chapter. Stains used include H&E, modified Gomori’s trichrome, ATPase for fiber typing, nicotinamide adenine dinucleotide dehydrogenase (NADH), succinate dehydrogenase (SDH), cytochrome oxidase, and other mitochondrial enzyme stains, PAS for glycogen, alizarin red S for calcium, alkaline phosphatase and nonspecific esterase for macrophages and denervated fibers, and lipid stains. When indicated, frozen sections also allow for immunostaining for cytoskeletal proteins, such as dystrophin (see Fig. 15-46) and the dystrophin-associated proteins. Certain abnormal structures, such as nemaline rods formed by expansion of Z bands, as seen in nemaline rod myopathy, are not visible in routine sections but are readily identified in frozen sections stained with modified Gomori’s trichrome.

The major disadvantage of frozen section histochemistry is that unless a neuromuscular disease laboratory is readily available to immediately process unfixed muscle samples, careful preparation for overnight shipping, on ice, in a moist but not overly wet environment, is necessary. Any delay in shipment or overwetting or overheating of the sample results in nondiagnostic samples. In addition, preparation of frozen sections is time and labor intensive, and in most cases only a single transverse section approximately 1 cm in diameter is examined. This can create a significant sampling error when evaluating a small sample of a large muscle in which lesions may not be evenly distributed.

Complete evaluation, which includes morphometric examination and calculation of the percentage and mean diameter of each fiber type, detects changes in the percentage of each fiber type and fiber atrophy or hypertrophy. But at this time, morphometric analysis is not routinely performed on samples submitted for diagnostic purposes.

Frozen section histochemistry is always a powerful tool for evaluation of muscle disease. But in many disorders, it is possible to obtain diagnostic sections from routinely processed muscle samples when appropriate sample selection, handling, and processing are performed, and sections are examined by a pathologist familiar with muscle pathology.

Electron Microscopy: Although much of what used to be determined by electron microscopy has been supplanted by newer immunohistochemical procedures, electron microscopic evaluation of muscle is still important. Various structural alterations, such as abnormalities of neuromuscular junctions, mitochondria, sarcomeric disarray, sarcotubular dilation, Z-line streaming, and cytoplasmic inclusions, may be best visualized, and in some cases only visualized, by this method. Sampling and handling methods to minimize contraction and other artefacts and to allow for precise transverse and longitudinal sections are imperative.

Physiologic Muscle Atrophy: Decrease in myofiber diameter and therefore in the overall muscle mass is a physiologic response to lack of use (disuse atrophy), cachexia, and aging. Type 2 fibers are preferentially affected (Web Fig. 15-4). Disuse atrophy occurs relatively slowly, and only in muscles not undergoing normal contraction, as is caused by severe lameness or in muscles of a limb that is splinted or enclosed in a cast. The degree of disuse atrophy will be variable, but typically is not as severe as the atrophy of cachexia or denervation (see later discussion). Disuse atrophy is often asymmetric. Muscle atrophy caused by cachexia can be profound, especially in cases of cancer cachexia in which increased circulating levels of TNF alter the muscle metabolism, favoring catabolic processes rather than anabolic processes. Cachexia also develops relatively slowly and causes symmetric muscle atrophy. Muscle atrophy caused by aging can be considered a milder form of cachexia. Starvation, malnutrition, and chronic renal and cardiac diseases can also result in cachexia.

Atrophy Caused by Endocrine Disease: Preferential atrophy of type 2 fibers causing symmetric muscle atrophy also occurs because of various endocrine disorders. The most common are hypothyroidism and hypercortisolism in dogs. Aging horses with pituitary dysfunction or tumors (leading to equine Cushing’s syndrome) often develop type 2 muscle fiber atrophy. Myofibers contain a high concentration of surface receptors for several hormones, and atrophy caused by endocrine disease reflects the intimate interrelationship between the endocrine and the muscular systems.

Denervation Atrophy: Denervation atrophy, also known by the misnomer neurogenic atrophy, is not uncommon in veterinary medicine. Maintenance of normal myofiber diameter depends on trophic factors generated by an intact associated nerve. Loss of neural input results in rapid muscle atrophy, and more than half the muscle mass of a completely denervated muscle can be lost in a few weeks. This trophic effect is not dependent on contractile activity because denervation atrophy is not a feature of neuromuscular junction disorders such as botulism and myasthenia gravis. In these disorders, there is a failure of neuromuscular transmission, but the nerve to the muscle is intact; therefore the muscle is technically still innervated. Generalized neuropathies or neuronopathies, such as equine motor neuron disease, result in widespread and symmetric muscle atrophy. More commonly, however, only select nerve damage is present, resulting in asymmetric muscle atrophy. One example is equine laryngeal hemiplegia (roaring) secondary to damage to the left recurrent laryngeal nerve (Fig. 15-18). It should be pointed out that purely demyelinating disorders of peripheral nerves can cause profound neuromuscular dysfunction, but axons are still intact. Associated myofibers are not technically denervated and therefore do not undergo denervation atrophy.

After denervation, fibers become progressively smaller in diameter as peripheral myofibrils disintegrate. If an atrophic fiber is surrounded by normal fibers, it will be pressed into an angular shape, called an angular atrophied fiber. The angular atrophied fibers of denervation atrophy most often occur either singly or in small contiguous groups (small group atrophy) (Fig. 15-19, A). In more severe denervating conditions, in which many fibers within muscle fascicles are undergoing denervation atrophy, there are no normal fibers to cause compression and angularity, and affected fibers occur as larger groups of small-diameter, rounded fibers (large group atrophy; Fig. 15-19, B). Although myofibrils disappear rapidly, muscle nuclei do not do so at the same rate, and therefore denervation atrophy is often associated with a notably increased concentration of myonuclei. The breakdown of glycogen in the myofiber is an early change in denervation atrophy, and therefore denervated fibers stain faintly or not at all with the PAS reaction.

A histologic diagnosis of denervation atrophy may be suspected, based on the characteristic features of routinely processed muscles, but is most reliably documented with histochemistry or immunohistochemistry to detect fiber types. The loss of a nerve fiber to a muscle results in atrophy of all myofibers innervated by that nerve. Because of the intermingling of motor units forming a mosaic pattern of fiber types, myofibers undergoing denervation atrophy are scattered in a section of muscle. Because the motor neuron determines the histochemical myofiber type and because denervating diseases typically involve both type 1 and type 2 neurons or nerves, atrophy of both type 1 and type 2 myofibers in muscle fasciculi is the hallmark of denervation atrophy (Fig. 15-20, A).

In denervation atrophy, histologic examination of the intramuscular nerves is warranted because it may reveal axonal degeneration or loss of myelinated fibers. Masson trichrome stain can be useful here because it will differentiate myelin (red) from collagen (blue). If the nerve damage does not incapacitate the animal and the muscle can still be used (e.g., in locomotion), the remaining innervated myofibers often undergo notable hypertrophy because of increased workload. Often, the hypertrophied fibers in chronic denervation are type 1. Even without fiber typing, a pattern of severe small or large group atrophy (see Fig. 15-19, A), especially if associated with notable fiber hypertrophy (see Fig. 15-19, B), is strongly suggestive of denervation atrophy. A finding of damage in an associated peripheral nerve is definitive.

Under many circumstances, denervated muscle fibers can be reinnervated by subterminal sprouting of axons from adjacent normal nerves. Reinnervation results in return to normal myofiber diameter, but reinnervation is often from sprouts of a different type of nerve. Because muscle fiber type is a function of the motor neuron, the newly innervated myofiber takes on the fiber type determined by that neuron. This process results in a loss of the normal arrangement of type 1 and 2 myofibers and the formation of groups of the same fiber type adjacent to each other, called fiber-type grouping (see Fig. 15-20). Thus fiber-type grouping is the hallmark of denervation followed by reinnervation. What appears to be fiber-type grouping can also occur because of fiber-type conversion (most often to type 1 fibers) in chronic myopathic conditions. Careful evaluation of the structure and function of peripheral nerves helps distinguish neuropathic from myopathic changes. If previously reinnervated fibers are denervated again, the pattern includes large groups of atrophied fibers of a single fiber type, a process known as type-specific group atrophy. Type-specific group atrophy is far less common in animals than in humans. Fiber-type grouping and type-specific group atrophy can only be detected by methods that distinguish fiber types. Changes occurring as a result of denervation and reinnervation are illustrated in Fig. 15-21.

Atrophy Caused by Congenital Myopathy: Congenital myopathy in children is often associated with selective type 1 fiber atrophy. This finding is less common in the congenital myopathies identified thus far in animals. Selective type 1 atrophy is, however, a feature of feline nemaline myopathy, an animal model of congenital nemaline myopathy in children.

Disturbance of Circulation: Given the numerous capillary anastomosis and rich collateral circulation of skeletal muscle, only disorders that result in occlusion of a major artery or that cause widespread intramuscular vascular damage will result in myofiber necrosis (Box 15-8). Vascular occlusion of a major artery, most often aortoiliac thrombosis, occurs most commonly in cats (thromboembolism) and horses (mural thrombosis). Intramuscular vascular damage occurs in many species, and there are a variety of causes.

The basic factor in determining the effect of ischemia on muscle is the differential susceptibility of the various cells forming the muscle as a whole. Myofibers are the most sensitive, satellite cells less sensitive, and fibroblasts the least sensitive to anoxia. Thus obstruction of the blood supply to an area of muscle leads first to myofiber necrosis, then to death of satellite cells, and finally to the death of all cells, including the stromal cells. The size of skeletal muscle infarcts depends on the size of the vessel obstructed and the duration of blockage. Because of the numerous anastomoses, blockage of capillaries causes less severe ischemia but can result in segmental myofiber necrosis, which is usually multifocal and if the cause is ongoing, polyphasic, with regenerating and necrotic myofibers. However, when larger arteries are blocked, whole areas of muscle, including the satellite cells, are killed, resulting in a monophasic necrosis and healing by fibrosis. Ischemia can also cause peripheral nerve damage and neuropathy, leading to denervation atrophy of intact myofibers.

Increased intramuscular pressure can occur in a recumbent animal of sufficient weight after a prolonged period of recumbency, either because of disease or general anesthesia. Myofiber necrosis caused by recumbency can occur because of (1) decreased blood flow as a result of compression of major arteries, (2) reperfusion injury causing massive calcium influx into muscle cells when the animal moves or is moved and the compression relieved, (3) increased intramuscular pressure causing compartment syndrome (see later definition), or (4) any combination of these factors. Localized myonecrosis caused by recumbency is common in horses, cattle, and pigs; occurs only in large breeds of dogs; and is virtually unheard of in cats. In downer cows, the weight of the body of the animal in sternal recumbency can cause ischemia of the pectoral muscles and of any muscles of the forelimbs or hindlimbs that are tucked under the body. Ewes in advanced pregnancy with twins or triplets can develop an ischemic necrosis of the internal abdominal oblique muscle, which can lead to muscle rupture. Plaster casts or bandages that are too tight can put external pressure on muscles, leading to ischemia. The duration of ischemia determines the severity of necrosis and the success of regeneration (see the section on Necrosis and Regeneration). Postanesthetic myopathy is a monophasic, multifocal necrosis. In the downer cow, the lesions are multifocal to locally extensive (Fig. 15-26) and, depending on the duration since the onset of recumbency, can be either monophasic or polyphasic.

Any severe insult, whether it be ischemia caused by recumbency or another myodegenerative disorder that causes myonecrosis within a muscle covered by a tight and nonexpansible fascia, can result in ischemic injury because early in the necrosis, there is increased intramuscular pressure. The resulting compromise of blood circulation leads to ischemic myodegeneration, which is known as compartment syndrome. The phenomenon of compartment syndrome is best illustrated in the anterior tibial muscle of humans after strenuous exercise. This condition is believed to be a consequence of swelling of the anterior tibial muscle, which is surrounded anteriorly by the inelastic anterior fascial sheath and posteriorly by the tibia. Swelling impedes blood supply, resulting in ischemia. A similar phenomenon occurs in muscles surrounded by tight fascia in animals, particularly horses. Horses that are recumbent because of general anesthesia can develop compartment syndrome affecting gluteal or lateral triceps muscles. Horses can also develop compartment syndrome in gluteal muscles because of exertional rhabdomyolysis and in temporal and masseter muscles because of selenium deficiency. Compartment syndrome is also possible in the temporal and masseter muscles of dogs with masticatory myositis.

Damage to intramuscular blood vessels will also cause myofiber necrosis. Vasculitis can cause areas of muscle damage (e.g., in horses with immune-mediated purpura hemorrhagica because of Streptococcus equi infection [see Fig. 15-33] and in pigs with erysipelas). Viral diseases that target blood vessels of many organs, such as bluetongue in sheep, can also affect muscle. Exotoxins produced by clostridial organisms cause myositis and severe localized vascular damage, leading to hemorrhage and myofiber necrosis (Table 15-3). The familial myopathy of Gelbvieh cattle is characterized by fibrinoid necrosis of intramuscular blood vessels and associated myonecrosis.

Nutritional Deficiency: Myofibers are particularly sensitive to nutritional deficiencies that result in the loss of antioxidant defense mechanisms. Nutritional myopathies are most common in livestock, including cattle, horses, sheep, and goats (Table 15-4). Although nutritional myopathy of livestock is often referred to as selenium/vitamin E deficiency, in the vast majority of cases, it is deficiency of selenium that is the cause of myofiber degeneration. The trace mineral selenium is a vital component of the glutathione peroxidase system, which helps to protect cells from oxidative injury. The high oxygen requirement combined with contractile activity makes striated muscle, both skeletal and cardiac, particularly sensitive to oxidative injury. Neonatal animals, which rely on stores of selenium accumulated during gestation, are most frequently affected. Affected muscle is pale as a result of necrosis (see Fig. 15-40); thus the common name white muscle disease. As should be evident from the previous discussion, a gross observation of pale muscle is not specific for necrosis caused by nutritional deficiency; therefore the term nutritional myopathy is much preferred.

Toxic Myopathies: Livestock are the animals most prone to develop a degenerative myopathy from the ingestion of a toxin (see Table 15-4). Myotoxins can be present in plants in pastures or hay and in plants or plant products in processed feed. Examples of toxic plants and plant products include Cassia (coffee senna), Karwinskia (coyotillo), Eupatorium (white snakeroot), Thermopsis spp., and gossypol present in cottonseed. Clinical signs are weakness, often leading to recumbency, and are accompanied by a moderate-to-severe increase in serum muscle enzyme concentrations. Gross and histologic findings of multifocal necrosis that can be either monophasic or polyphasic are typical. Diagnosis is based on identification of causative plants within feed, pasture, or stomach contents or when available, detection of toxic compounds in stomach content or liver.

Ionophore antibiotics, such as monensin, lasalocid, maduramicin, and narasin, are often added to ruminant feeds to enhance growth. Ionophores form lipid soluble dipolar reversible complexes with cations and allow movement of cations across cell membranes, often against the concentration gradient. This causes a disruption of ionic equilibrium that can be detrimental, especially to excitable tissue such as the nervous system, heart, and skeletal muscle. Ionophore toxicity results in calcium overload and death of skeletal (see Figs. 15-13, B, and 15-34) and cardiac muscle. Most domestic ruminants are quite tolerant of moderate ionophore levels, but toxicity occurs at very high levels. Most cases of ionophore toxicity involve the ingestion of monensin. The LD₅₀ (the dose at which 50% of animals die) of monensin in cattle is 50 to 80 mg/kg, and the LD₅₀ for sheep and goats is 12 to 24 mg/kg. Horses are exquisitely sensitive to ionophores and even very low levels are toxic, with an LD₅₀ for monensin of only 2 to 3 mg/kg of body weight.

Exertional Myopathies: The ionic and physical events associated with myofiber contraction can under certain circumstances predispose a myofiber to necrosis. Exercise-induced myonecrosis, which can be massive, can occur because of simple overexertion. This outcome is well known in the capture and restraint of nondomesticated species, a syndrome known as capture myopathy. More often, however, exercise-induced myofiber damage occurs in animals with preexisting conditions such as selenium deficiency, muscular dystrophy, severe electrolyte depletion, or glycogen storage disease. The term exertional rhabdomyolysis (also known as exertional myopathy, azoturia, setfast, blackwater, Monday morning disease, and tying up) has long been applied to a syndrome recognized in horses (see Fig. 15-36). Only recently have underlying myopathic conditions been identified as the most common predisposing cause of equine exertional rhabdomyolysis (see the section on Muscular Disorders of the Horse). A similar disorder affects working dogs such as racing sled dogs and greyhounds, the cause of which is still unclear.

Trauma: External trauma to muscle includes crush injury, lacerations and surgical incisions, tearing caused by excessive stretching or exercise, burns, gunshot and arrow wounds, and certain injections. Some of these result in complete or partial rupture of a large muscle. The diaphragm is the most common muscle to rupture and in dogs and cats is most often the result of a sudden increase in intraabdominal pressure such as from being hit by a car. In horses, diaphragmatic rupture is thought to occur most often during falls in which the pressure of the abdominal viscera causes diaphragmatic damage. A partial rupture of a muscle results in a tear in the fascial sheath, through which the muscle can herniate during contraction. In racing greyhounds, spontaneous rupture of muscles, such as the longissimus, quadriceps, biceps femoris, gracilis, triceps brachii, and gastrocnemius, can occur during strenuous exercise. In horses, damage to the origin of the gastrocnemius muscle has been linked to overexertion during exercise or while struggling to rise. Tearing of muscle fibers occurs in the adductor muscles of the hind limbs of cattle doing the “splits” (sudden bilateral abduction) on a slippery floor. Because there is often extensive disruption of the myofibers’ basal laminae, most of the healing is accomplished by fibrosis. If muscle trauma is accompanied by fractures of bones and the animal moves the limb, further trauma by laceration by sharp bone fragments can result.

An abnormal response to localized muscle trauma is thought to be a possible underlying cause of two uncommon reactions of muscle: myositis ossificans and musculoaponeurotic fibromatosis. The term myositis ossificans is a misnomer, as the lesion does not involve inflammation, but it has attained the status of acceptance by common usage. Myositis ossificans is a focal lesion usually confined to a single muscle and has been seen in horses, dogs, and humans. The lesion is essentially a focal zone of fibrosis with osseous metaplasia, often with a zonal pattern. The central zone contains proliferating undifferentiated cells and fibroblasts; the middle one, osteoblasts depositing osteoid and immature bone; and the outer one, trabecular bone, which may be being remodeled by osteoclasts. These lesions can cause pain and lameness, which are often cured by surgical excision. A connective tissue disorder in cats, fibrodysplasia ossificans progressiva, has been inappropriately called myositis ossificans. Musculoaponeurotic fibromatosis has so far been described only in horses and humans. It is a progressive intramuscular fibromatosis that has also been called a desmoid tumor. Musculoaponeurotic fibromatosis is not, however, considered to be a true neoplastic process. Progressive dissecting intramuscular fibrosis accompanied by myofiber atrophy are the characteristic features. In most cases, the extent of intramuscular involvement makes surgical excision impossible, although wide excision of early lesions has proved to be curative.

Bacterial: Bacterial infections of muscle are not uncommon, particularly in livestock. Bacteria can cause suppurative and necrotizing, suppurative and fibrosing, hemorrhagic, or granulomatous lesions (Table 15-5). Bacterial infection can be introduced by direct penetration (wounds or injections), hematogenously, or by spread from an adjacent cellulitis, fasciitis, tendonitis, arthritis, or osteomyelitis (see the section on Portals of Entry).

Various clostridial species, particularly Clostridium perfringens, Clostridium chauvoei, Clostridium septicum, and Clostridium novyi, can elaborate toxins (see Table 15-3) that damage myofibers and intramuscular vasculature, resulting in hemorrhagic myonecrosis (see Figs. 15-32 and 15-38). Toxemia is typical and often lethal. Clostridial myositis is most common in cattle and horses. Clostridial myositis has also been called gas gangrene and malignant edema in horses and blackleg in cattle.

Pyogenic bacteria introduced into a muscle usually cause localized suppuration and myofiber necrosis. This may resolve completely or become localized to form an abscess. In some cases, the infection can spread down the fascial planes (see Fig. 15-12). For example, a nonsterile intramuscular injection into the gluteal muscles of cattle can cause an infection that extends down the fascial planes of the muscles of the femur and tibia and erupts to the surface through a sinus proximal to the tarsus. Although the majority of inflammation involves fascial planes, some bacteria extend into and cause necrosis of adjacent muscle fasciculi. Streptococcus zooepidemicus (horses), Arcanobacterium pyogenes (cattle and sheep), and Corynebacterium pseudotuberculosis (horses, sheep, and goats) are common causes of muscle abscesses. After bite wounds from other cats, cats can develop cellulitis caused by Pasteurella multocida that extends into the adjacent muscle.

Bacteria causing single or multiple granulomas (focal or multifocal granulomatous myositis) are relatively uncommon. Most such lesions are caused by Mycobacterium bovis (tuberculosis), usually in cattle and pigs, but this disease is rare in North America.

Chronic fibrosing nodular myositis of the tongue musculature in cattle is the result of infection with Actinobacillus lignieresii (wooden tongue) or Actinomyces bovis (the agent causing lumpy jaw). A similar lesion caused by Staphylococcus aureus is known as botryomycosis and is most commonly seen in horses and pigs. It is most often wound related and can occur at a variety of sites. Histologically, actinobacillosis, actinomycosis, and botryomycosis are similar in that the lesions are encapsulated inflammatory lesions containing a central focus of “radiating clubs” of amorphous eosinophilic material associated with bacteria and neutrophils (Splendore-Hoeppli reaction). Neutrophils admixed with macrophages (pyogranulomatous inflammation) can also be seen. Gram-stained tissue can be used to differentiate between the clusters of Gram-positive cocci in Staphylococcus infection, the Gram-positive bacilli causing actinomycosis (Actinomyces bovis), and the Gram-negative bacilli causing actinobacillosis (Actinobacillus lignieresii).

Viral: Relatively few of these are recognized in veterinary medicine. Spontaneous ones are listed in Table 15-6. Gross lesions may or may not be visible and if present, are small, poorly defined foci or streaks. Muscle lesions induced by viruses are either infarcts secondary to a vasculitis, as seen in bluetongue in sheep, or multifocal necrosis, presumably because of a direct effect of the virus on the myofibers.

Parasitic: Parasitic infections of the skeletal muscles of domestic animals are not uncommon and include protozoal organisms and nematodes. The most important ones are listed in Table 15-7 and are discussed under the appropriate species heading. Most parasitic diseases have little pathologic or economic importance, with the exceptions of Neospora caninum, Hepatozoon americanum, and Trypanosoma cruzi in dogs and Trichinella spiralis in pigs.

As the name Sarcocystis suggests, intramyofiber protozoal cysts caused by Sarcocystis spp. are a common finding. This protozoal organism is a stage in the life cycle of an intestinal coccidium of carnivores that uses birds, reptiles, rodents, pigs, and herbivores as an intermediate host. Ingestion of oocysts by an intermediate host releases sporozoites that penetrate through the intestinal wall, enter blood vessels, and are hematogenously disseminated and invade tissue, including muscle. This parasite rarely causes clinical disease and is therefore most often considered an incidental finding. Sarcocystis infection of muscle is seen most often in horses, cattle, and small ruminants and occasionally in cats. Because they are intracellular, cysts are protected from the host’s defense mechanisms; thus there is no inflammatory response (Fig. 15-27).

Immune-Mediated: Immunologically induced myositis, not associated with vascular injury, has been recognized primarily in the dog. Rarely, immune-mediated myositis occurs in cats and horses. Infiltrating lymphocytes, most often cytotoxic T lymphocytes, are the cause of myofiber injury. Although cytotoxic T lymphocytes are the effector cells causing myofiber damage, the inflammatory infiltrate is a mixture of lymphocyte types. The characteristic histologic pattern of immune-mediated myositis is an interstitial and perivascular lymphocytic infiltration (Fig. 15-28, A, see also Fig. 15-48), often with invasion of intact myofibers by lymphocytes (Fig. 15-28, B). A variety of forms of immune-mediated myositis occur in the dog and can be localized to specific muscles, presumably because of unique myosin isoforms within those muscles. These are listed in Table 15-8. Acquired myasthenia gravis is also an immune-mediated disease and is included in this table for completeness, but this is a disorder causing damage to the neuromuscular junction rather than to myofibers. In cats, feline immunodeficiency virus infection is a cause of immune-mediated myositis. In horses, lesions consistent with immune-mediated myositis are occasionally found after exposure to Streptococcus equi ssp. equi or infection with equine influenza virus. It should be pointed out that small perivascular and interstitial infiltrates of lymphocytes, with no apparent myofiber damage, are a frequent incidental finding in equine muscle.

Immune-mediated vasculitis resulting in muscle injury occurs in horses and is known as purpura hemorrhagica. Purpura hemorrhagica has been classically associated with Streptococcus equi ssp. equi, but other bacteria, such as Corynebacterium pseudotuberculosis, can also cause purpura hemorrhagica.

Anatomic Defects: Anatomic defects in skeletal muscle are apparent at birth or soon thereafter. These defects can be either genetic or acquired and result from either abnormal in utero muscle development or abnormal innervation.

Muscular Dystrophy: The term muscular dystrophy has been grossly misused in the veterinary literature. In the 1930s, the term nutritional muscular dystrophy was applied to a disease more appropriately classified as nutritional myopathy, and the misuse of this term has been a source of confusion for years as to exactly what is meant by muscular dystrophy. Using the definition applied to humans, muscular dystrophy is an inherited, progressive, degenerative primary disease of the myofiber characterized histologically by ongoing myofiber necrosis and regeneration (polyphasic necrosis). Several types of muscular dystrophy occur in humans and animals. The enormous recent advances in genetic and molecular characterization of muscle diseases have resulted in defining their exact genetic defects, such as those in the dystrophin gene responsible for Duchenne’s muscular dystrophy and trinucleotide repeat sequences in myotonic dystrophy, and in the reclassification of others. Similarly, reevaluation of some inherited disorders previously classified as muscular dystrophy, such as muscular dystrophy in sheep and cattle, suggests that they would be better classified as progressive congenital myopathies.

Congenital Myopathies: Those inherited disorders of muscle that do not qualify as anatomic defects, muscular dystrophy, myotonia, or a metabolic myopathy (see later discussion) are classified as congenital myopathies. These include structural defects leading to abnormal myofiber cytoarchitecture. In some cases, the defective gene is known, whereas the cause of others remains undetermined.

Myotonia (Channelopathies): Myotonia is defined as the inability of skeletal muscle fibers to relax, resulting in spasmodic contraction. Various inherited myotonic conditions have been recognized in humans and animals for many years. Only recently has the basis for many of these myopathies been determined. Most have been found to be related to inherited defects resulting in abnormal ion channel function. Maintenance of ionic equilibrium and control of the ionic fluxes of excitable tissue, such as muscle, are critical to normal muscle functioning. A variety of sarcolemmal ion channels exist that control fluxes of ions such as sodium, potassium, chloride, and calcium. Defective sodium or chloride channels most often result in myotonia.

Metabolic Myopathies: Inherited disorders of muscle metabolism (see Web Table 15-2) are characterized by reduced muscle cell energy production. Clinical signs include exercise intolerance, exercise-induced muscle cramps, and rhabdomyolysis (acute segmental myofiber necrosis). Metabolic defects can involve glycogen metabolism, fatty acid metabolism, or mitochondrial function. Metabolic disorders often cause increased blood lactate after exercise. Inheritance patterns vary. Glycolytic, glycogenolytic, and nonmitochondrial DNA–encoded enzyme defects are generally inherited in an autosomal recessive manner. Defects involving mitochondrial DNA–encoded enzymes are inherited through the dam because all mitochondria are contributed by the oocyte.

The pathways of glycolysis and glycogenolysis are complex, involving a cascade of enzymatic reactions. Deficiency of a glycolytic or glycogenolytic enzyme leads to accumulation of glycogen and in some cases glycogen-related proteoglycans. There are many different types of glycogen storage diseases and their categorization is dependent on which enzyme is deficient. Of the types of glycogenoses recognized in humans, five types (II, III, IV, V, and VII) cause glycogen accumulation in muscle. Of the glycogenoses affecting muscle, only types II (acid maltase deficiency), IV (glycogen branching enzyme deficiency), V (myophosphorylase deficiency), and VII (phosphofructokinase deficiency) have so far been recognized in animals. Storage diseases in which glycogen accumulates in muscle have been described in horses, cattle, sheep, dogs, and cats.

Inherited lipid storage myopathies have not yet been described in animals, although dogs appear to have a predilection for development of neuromuscular weakness because of acquired lipid storage myopathy with concurrent reduction in skeletal muscle carnitine activity. Mitochondrial myopathies are rarely recognized in animals, perhaps because of the difficulty in confirming mitochondrial defects. A few such disorders have been described in dogs, and a mitochondrial myopathy has been reported in one Arabian horse. Mitochondrial disorders may affect only muscle, or muscle involvement may be part of an encephalomyopathic condition.

Malignant Hyperthermia (MH): MH is a condition characterized by unregulated release of calcium from the sarcoplasmic reticulum, leading to excessive myofiber contraction that generates heat, resulting in a severe increase in body temperature. MH is often fatal. In humans, pigs, horses, and dogs, a congenital defect in the sarcoplasmic reticulum calcium-release channel, the ryanodine receptor, causes dysregulation of excitation-contraction coupling leading to MH. Episodes in affected individuals can be triggered by general anesthetic agents, especially halothane, or by stress, thus the name porcine stress syndrome for the disorder in pigs (see Fig. 15-43).

A MH-like condition can also occur because of other myopathic conditions, especially those that result in uncoupling of mitochondrial oxidative phosphorylation from the electron transport chain. Inherently uncoupled mitochondria within brown fat are the physiologic basis for production of heat during breakdown of this fat in neonates, and pathologically uncoupled or loosely coupled mitochondria in muscle as a result of an underlying myopathy release energy as heat.

Gross and microscopic lesions are described in the discussion on the disorder in the section on Disorders of Pigs.